Multidrug resistant bacteria continue to be a health-care burden in both hospital and community settings. Remarkably, in the past fifty years, only a few new chemical classes of antibiotics have reached the clinic. Existing antibiotics are directed at a small number of targets, principally cell wall, DNA and protein biosynthesis. Indeed, multidrug resistance among bacterial pathogens is thought to be due in large part to the limited repertoire of antibacterial chemical matter that eradicate bacteria using a narrow range of mechanisms. Bacterial genomics heralded a genes-to-drugs approach where new targets would lead to new chemical matter that inhibit bacterial growth with new mechanisms of action and are unsusceptible to existing resistance mechanisms. Unfortunately, there have been no new drugs with this approach. Among the most significant obstacles to modern antibacterial drug discovery has been a struggle to understand the complexity of the biology that underlies various targets. In efforts ongoing, the Brown Labresearch group is working to explore largely uncharted aspects of complex biology in bacteria. We are working to comprehend poorly understood aspects of cell wall biosynthesis, in particular the biogenesis of wall teichoic acid in Gram-positive bacteria. We are also characterizing conserved and enigmatic proteins that have vital roles in the assembly of ribosomal subunits in bacteria. Further we have embarked on ambitious efforts to uncover new chemical probes of bacteria and to chart chemical-genetic interactions for known and novel antibacterial compounds on a genomic scale. Together the ultimate goal of these studies is to contribute to fresh directions for new antibacterial therapeutics.